Matthew D. Snape

Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2 ⁺ γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.

OBJECTIVES: Human metapneumovirus (hMPV) and parainfluenza virus type 3 (PIV3) are common respiratory illnesses in children. The safety and immunogenicity of an investigational mRNA-based vaccine, mRNA-1653, encoding membrane-anchored fusion proteins of hMPV and PIV3, was evaluated in hMPV/PIV3-seropositive children. METHODS: In this phase 1b randomized, observer-blind, placebo-controlled, dose-ranging study, hMPV/PIV3-seropositive children were enrolled sequentially into 2 dose levels of mRNA-1653 administered 2 months apart; children aged 12 to 36 months were randomized (1:1) to receive 10-μg of mRNA-1653 or placebo and children aged 12 to 59 months were randomized (3:1) to receive 30-μg of mRNA-1653 or placebo. RESULTS: Overall, 27 participants aged 18 to 55 months were randomized; 15 participants received 10-μg of mRNA-1653 (n = 8) or placebo (n = 7), whereas 12 participants received 30-μg of mRNA-1653 (n = 9) or placebo (n = 3). mRNA-1653 was well-tolerated at both dose levels. The only reported solicited local adverse reaction was tenderness at injection site; solicited systemic adverse reactions included grade 1 or 2 chills, irritability, loss of appetite, and sleepiness. A single 10-μg or 30-μg mRNA-1653 injection increased hMPV and PIV3 neutralizing antibody titers (geometric mean fold-rise ratio over baseline: hMPV-A = 2.9–6.1; hMPV-B = 6.2–13.2; PIV3 = 2.8–3.0) and preF and postF binding antibody concentrations (geometric mean fold-rise ratio: hMPV preF = 5.3–6.1; postF = 4.6–6.5 and PIV3 preF = 13.9–14.2; postF = 11.0–12.1); a second injection did not further increase antibody levels in these seropositive children. Binding antibody responses were generally preF biased. CONCLUSIONS: mRNA-1653 was well-tolerated and boosted hMPV and PIV3 antibody levels in seropositive children aged 12 to 59 months, supporting the continued development of mRNA-1653 or its components for the prevention of hMPV and PIV3.

Background: Three hexavalent (DTaP-IPV-Hib-HepB) vaccines are licensed in Europe, only one of which (Vaxelis, Hex-V), uses a meningococcal outer membrane protein complex as a carrier protein for Hemophilus influenza type b (Hib), creating potential interactions with the meningococcal vaccine 4CMenB. Methods: In this single-center open-label randomized trial, infants were randomized in a 1:1 ratio to receive Hex-V or an alternative hexavalent vaccine (Infanrix-Hexa, Hex-IH) at 2, 3, and 4 months with 4CMenB (2, 4, and 12 months) in the UK routine immunization schedule. The primary outcome was noninferiority of geometric mean concentrations (GMCs) of anti-PRP (Hib) IgG at 5 months of age. Secondary outcomes included safety, reactogenicity, and immunogenicity of other administered vaccines measured at 5 and 13 months of age. Results: Of the 194 participants enrolled, 96 received Hex-V and 98 Hex-IH. Noninferiority of anti-PRP IgG GMCs at 5 months of age in participants receiving Hex-V was established; GMCs were 23-times higher following three doses of Hex-V than three doses of Hex-IH (geometric mean ratio (GMR) 23.25; one-sided 95% CI 16.21, -). 78/85 (92%) of Hex-V recipients and 43/87 (49%) of Hex-IH recipients had anti-PRP antibodies ≥1.0 µg/mL. At 5 months of age serum, bactericidal activity titers against MenB strain 5/99 were higher following Hex-V than Hex-IH (GMR 1.56; 95% CI, 1.13–2.14). The reactogenicity profile was similar in both groups. Conclusions: These data support flexibility in the use of either Hex-IH or Hex-V in infant immunization schedules containing 4CMenB, with the possibility that Hex-V may enhance protection against Hib.

The etiology of type 1 diabetes has polygenic and environmental determinants that lead to autoimmune responses against pancreatic β cells and promote β cell death. The autoimmunity is considered silent without metabolic consequences until late preclinical stages,and it remains unknown how early in the disease process the pancreatic β cell is compromised. To address this, we investigated preprandial nonfasting and postprandial blood glucose concentrations and islet autoantibody development in 1,050 children with high genetic risk of type 1 diabetes. Pre- and postprandial blood glucose decreased between 4 and 18 months of age and gradually increased until the final measurements at 3.6 years of age. Determinants of blood glucose trajectories in the first year of life included sex, body mass index, glucose-related genetic risk scores, and the type 1 diabetes–susceptible INS gene. Children who developed islet autoantibodies had early elevations in blood glucose concentrations. A sharp and sustained rise in postprandial blood glucose was observed at around 2 months prior to autoantibody seroconversion, with further increases in postprandial and, subsequently, preprandial values after seroconversion. These findings show heterogeneity in blood glucose control in infancy and early childhood and suggest that islet autoimmunity is concurrent or subsequent to insults on the pancreatic islets.

In this report, we present live neutralisation titres against SARS-CoV-2 Omicron variant, compared with neutralisation against Victoria, Beta and Delta variants. Sera from day-28 post second-dose were obtained from participants in the Com-COV2 study who had received a two-dose COVID-19 vaccination schedule with either AstraZeneca (AZD1222) or Pfizer (BNT162b2) vaccines. There was a substantial fall in neutralisation titres in recipients of both AZD1222 and BNT16b2 primary courses, with evidence of some recipients failing to neutralise at all. This will likely lead to increased breakthrough infections in previously infected or double vaccinated individuals, which could drive a further wave of infection, although there is currently no evidence of increased potential to cause severe disease, hospitalization or death.